BHD Research Blog

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BHD Research Blog is the official blog of BHDSyndrome.org, the primary online resource for anyone interested in Birt-Hogg-Dubé Syndrome, a rare genetic condition linked to benign skin growths, collapsed lung and kidney cancers. In the BHD Research Blog, we focus on analysing current research in BHD and related fields, as well as considering wider issues relating to rare diseases.

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  • May 18, 2012
  • 04:00 AM
  • 27 views

mTOR signalling and BHD-associated lung and kidney lesions

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Pulmonary cysts and pneumothorax are key indicators of BHD syndrome. However, very little is known about the pathophysiology of these lung cysts. A recent Japanese study of 9 families has now shown that not only are BHD cysts different from … Continue reading →... Read more »

Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, Hsu YH, Fujii T, Okada A, Kuroda N.... (2012) Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families. The American journal of surgical pathology, 36(4), 589-600. PMID: 22441547  

  • May 11, 2012
  • 09:17 AM
  • 60 views

Video Interview: Lindsay Middelton – National Cancer Institute, NIH, USA

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

This week we introduce Lindsay Middelton R.N., C.G.C, who is a genetic counsellor with the National Cancer Institute (NCI) of the National Institutes of Health, USA. Lindsay is part of the Urologic Oncology Branch at the NCI, which treats patients … Continue reading →... Read more »

Middelton L, Dimond E, Calzone K, Davis J, & Jenkins J. (2002) The role of the nurse in cancer genetics. Cancer nursing, 25(3), 196-206. PMID: 12040228  

Singer EA, Bratslavsky G, Middelton L, Srinivasan R, & Linehan WM. (2011) Impact of genetics on the diagnosis and treatment of renal cancer. Current urology reports, 12(1), 47-55. PMID: 21128028  

Zbar B, Glenn G, Merino M, Middelton L, Peterson J, Toro J, Coleman J, Pinto P, Schmidt LS, Choyke P.... (2007) Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development. The Journal of urology, 177(2), 461. PMID: 17222609  

  • May 4, 2012
  • 04:00 AM
  • 66 views

DNA methylation and kidney cancer

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Mutations in genes such as FLCN and VHL are implicated in the development of renal cell carcinoma (RCC). However, DNA methylation and transcriptional silencing at gene promoters can also be involved, as is the case with RASSF1A, which is rarely … Continue reading →... Read more »

Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S.... (2003) Inactivation of BHD in sporadic renal tumors. Cancer research, 63(15), 4583-7. PMID: 12907635  

Ricketts CJ, Morris MR, Gentle D, Brown M, Wake N, Woodward ER, Clarke N, Latif F, & Maher ER. (2012) Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. Epigenetics : official journal of the DNA Methylation Society, 7(3), 278-90. PMID: 22430804  

  • April 27, 2012
  • 06:36 AM
  • 65 views

Patient and Family sessions at the Fourth BHD Symposium

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Around 30 patients and family members participated in the Fourth BHD Symposium in Cincinnati, Ohio last month. Such a record turnout had a significant effect on the flow of the Symposium – for example, by providing researchers with many opportunities … Continue reading →... Read more »

  • April 6, 2012
  • 04:00 AM
  • 53 views

Characterisation of the RCC susceptibility locus on chromosome 11

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

A blog post from January last year described a paper by Purdue et al. (2011) in which a genome-wide association study (GWAS) identified two renal cell carcinoma (RCC) susceptibility loci within HIF2α (on chromosome 2) and an uncharacterised intergenic region (on … Continue reading →... Read more »

  • March 16, 2012
  • 12:27 PM
  • 118 views

Single-cell exome sequencing of a ccRCC sample

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Recent advances in DNA sequencing have led to the discovery of genes and mutations which drive tumourigenesis. In this blog, we have previously described papers by Varela et al. (2011), Dalgliesh et al. (2011) and Guo et al. (2011) which … Continue reading →... Read more »

  • March 9, 2012
  • 03:00 AM
  • 177 views

Lab-profile: Professor Arnim Pause – McGill University, Canada

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Our lab-profile for this month introduces the work of Professor Arnim Pause, an Associate Professor in the Department of Biochemistry and a Canada Research Chair in Molecular Oncology at McGill University, Canada. Much of Professor Pause’s early work involved researching … Continue reading →... Read more »

Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, Crosby K, Pomerleau V, Uetani N, & Pause A. (2010) Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin. Journal of medical genetics, 47(3), 182-9. PMID: 19843504  

Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD, & Pause A. (1999) Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. Proceedings of the National Academy of Sciences of the United States of America, 96(22), 12436-41. PMID: 10535940  

  • March 2, 2012
  • 04:33 AM
  • 136 views

The role of HIF-2α in renal cell carcinoma

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Hypoxia Inducible Factor (HIF) regulates key processes within the cell and its dysregulation is involved in the development of renal cell carcinoma (RCC), including those associated with VHL, HLRCC, TSC and also BHD syndrome. HIF is a potential therapeutic target … Continue reading →... Read more »

Schietke RE, Hackenbeck T, Tran M, Günther R, Klanke B, Warnecke CL, Knaup KX, Shukla D, Rosenberger C, Koesters R.... (2012) Renal Tubular HIF-2α Expression Requires VHL Inactivation and Causes Fibrosis and Cysts. PloS one, 7(1). PMID: 22299048  

Rosenberger C, Mandriota S, Jürgensen JS, Wiesener MS, Hörstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, & Eckardt KU. (2002) Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. Journal of the American Society of Nephrology : JASN, 13(7), 1721-32. PMID: 12089367  

Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ.... (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer cell, 20(4), 511-23. PMID: 22014576  

Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, Pugh CW, Maxwell PH, Harris AL, & Ratcliffe PJ. (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and cellular biology, 25(13), 5675-86. PMID: 15964822  

  • February 17, 2012
  • 03:00 AM
  • 117 views

Overview of the NCRI, BTS and BAD meetings

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

In November last year, the 7th National Cancer Research Institute (NCRI) Cancer Conference was held in Liverpool, UK. This conference focussed on all aspects of cancer research, from basic research to clinical care. Of note, Prof. Dr. Michael Hall from … Continue reading →... Read more »

Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A.... (2011) Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature, 477(7363), 225-8. PMID: 21849978  

  • February 3, 2012
  • 10:17 AM
  • 157 views

Gene therapy in VHL-null cells using human artificial chromosomes

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Last month, our conference summary highlighted some of the work that is taking place in the field of gene therapy. Currently, many advanced gene therapy systems are derived from viruses, such as the adenovirus and lentivirus. However, these viral vectors … Continue reading →... Read more »

Kim JH, Kononenko A, Erliandri I, Kim TA, Nakano M, Iida Y, Barrett JC, Oshimura M, Masumoto H, Earnshaw WC.... (2011) Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells. Proceedings of the National Academy of Sciences of the United States of America, 108(50), 20048-53. PMID: 22123967  

  • January 27, 2012
  • 04:45 AM
  • 145 views

Video Interview: Dr Tim Cash – Abramson Family Cancer Research Institute

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

This week we highlight the work of Dr Tim Cash, who worked on BHD syndrome as part of his PhD studies in the lab of Professor Celeste Simon at the Abramson Family Cancer Research Institute, University of Pennsylvania. Dr Cash … Continue reading →... Read more »

  • January 20, 2012
  • 05:31 AM
  • 124 views

FLCN-FNIP2-AMPK and MNU-induced apoptosis

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

DNA repair proteins appear to play a significant role in both the development and progression of renal cell carcinoma, as has been discussed in earlier blog posts from 2010 and 2011. These proteins are responsible for repairing DNA lesions caused … Continue reading →... Read more »

  • December 30, 2011
  • 06:33 AM
  • 118 views

The ubiquitin-mediated proteolysis pathway and clear cell RCC

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Mutations in VHL are known to be associated with the development of clear cell renal cell carcinoma (ccRCC), and recent sequencing studies have identified several genes involved in chromatin regulation that are also frequently mutated in ccRCC (Dalgliesh et al., 2010; … Continue reading →... Read more »

Dalgliesh, G., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C.... (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 463(7279), 360-363. DOI: 10.1038/nature08672  

Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J.... (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature, 469(7331), 539-42. PMID: 21248752  

  • December 22, 2011
  • 04:20 AM
  • 105 views

Video Interview: Dr Seung-Beom Hong – University of Pennsylvania, USA

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

This week we would like to introduce Dr Seung-Beom Hong, a post-doctoral researcher in the lab of Professor Vera Krymskaya at the University of Pennsylvania. Dr Hong was part of the group at the NIH that helped to identify and … Continue reading →... Read more »

Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, Haines DC, Merino MJ, Hong SB, Yamaguchi TP.... (2009) Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proceedings of the National Academy of Sciences of the United States of America, 106(44), 18722-7. PMID: 19850877  

Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, & Schmidt LS. (2008) Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene, 415(1-2), 60-7. PMID: 18403135  

Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL.... (2006) Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(42), 15552-7. PMID: 17028174  

Hong SB, Furihata M, Baba M, Zbar B, & Schmidt LS. (2006) Vascular defects and liver damage by the acute inactivation of the VHL gene during mouse embryogenesis. Laboratory investigation; a journal of technical methods and pathology, 86(7), 664-75. PMID: 16652107  

  • December 16, 2011
  • 04:29 AM
  • 988 views

Estimating the risk of pneumothorax and renal cell carcinoma in BHD patients

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Many studies into BHD syndrome have investigated the prevalence of pneumothorax and renal cell carcinoma amongst FLCN mutation carriers. Previous estimations of the RCC risk have varied from 6.5% to 34% (Toro et al., 2008), and for pneumothorax, from 24% … Continue reading →... Read more »

Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, Turner ML, Choyke PL, Sharma N, Peterson J.... (2005) Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. American journal of human genetics, 76(6), 1023-33. PMID: 15852235  

Toro JR, Pautler SE, Stewart L, Glenn GM, Weinreich M, Toure O, Wei MH, Schmidt LS, Davis L, Zbar B.... (2007) Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome. American journal of respiratory and critical care medicine, 175(10), 1044-53. PMID: 17322109  

Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, Leter EM, van Os TA, van Grieken NC, Jaspars EH.... (2011) Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. British journal of cancer, 105(12), 1912-9. PMID: 22146830  

Pavlovich CP, Walther MM, Eyler RA, Hewitt SM, Zbar B, Linehan WM, & Merino MJ. (2002) Renal tumors in the Birt-Hogg-Dubé syndrome. The American journal of surgical pathology, 26(12), 1542-52. PMID: 12459621  

Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER.... (2009) Birt-Hogg-Dubé syndrome: diagnosis and management. The lancet oncology, 10(12), 1199-206. PMID: 19959076  

  • December 2, 2011
  • 05:59 AM
  • 194 views

A HIF-independent pathway for tumourigenesis in HLRCC

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

HLRCC, caused by mutations in FH, predisposes patients to develop papillary renal cell carcinoma. FH-deficient cells have an accumulation of fumarate, which leads to the stabilisation of HIF-α subunits and therefore an increase in HIF-α levels. An increased expression of … Continue reading →... Read more »

Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, Min BW, Tan MH, Zhang Z, Yang XJ.... (2011) An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer cell, 20(4), 511-23. PMID: 22014576  

Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED, Jerby L, Micaroni M, Chaneton B, Adam J, Hedley A.... (2011) Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature, 477(7363), 225-8. PMID: 21849978  

  • November 25, 2011
  • 04:41 AM
  • 176 views

TSC clinical trials

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

In our last conference summary, it was noted that a number of clinical trials are underway to find an effective treatment for tuberous sclerosis complex (TSC). These trials use the mTORC1 inhibitors rapamycin and everolimus to compensate for mutations in … Continue reading →... Read more »

Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J.... (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. The New England journal of medicine, 358(2), 140-51. PMID: 18184959  

Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, Watson PC, Howe CJ, Doyle T, Pointon K.... (2011) Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clinical cancer research : an official journal of the American Association for Cancer Research, 17(12), 4071-81. PMID: 21525172  

Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, & Franz DN. (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. The New England journal of medicine, 363(19), 1801-11. PMID: 21047224  

McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM.... (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364(17), 1595-606. PMID: 21410393  

  • November 18, 2011
  • 04:00 AM
  • 149 views

Degradation of HIF-1α by Hypericin

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

Hypoxia inducible factor (HIF) regulates processes such as cell proliferation and metabolism, and it has been implicated in tumour growth in several disorders such as VHL and TSC. Preston et al. (2010) demonstrated that HIF-1α activity was increased in FLCN-null … Continue reading →... Read more »

Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, & Neckers LM. (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. The Journal of biological chemistry, 277(33), 29936-44. PMID: 12052835  

  • November 4, 2011
  • 05:12 AM
  • 257 views

Lab-profile: prof. dr. Maurice van Steensel – University Hospital Maastricht

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

In this month’s lab-profile we introduce Professor Maurice van Steensel, a Professor of genetic dermatology at the University Hospital Maastricht. Professor van Steensel leads a research group studying the role of FLCN in BHD syndrome and he is also a … Continue reading →... Read more »

Claessens T, Weppler SA, van Geel M, Creytens D, Vreeburg M, Wouters B, & van Steensel MA. (2010) Neuroendocrine carcinoma in a patient with Birt-Hogg-Dubé syndrome. Nature reviews. Urology, 7(10), 583-7. PMID: 20842188  

Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER.... (2009) Birt-Hogg-Dubé syndrome: diagnosis and management. The lancet oncology, 10(12), 1199-206. PMID: 19959076  

  • October 28, 2011
  • 05:44 AM
  • 215 views

Conference reports

by Vicki Colledge, Sanjay Thakrar, Galina Shyndriayeva in BHD Research Blog

In July, the Beatson International Cancer Conference took place at The Beatson Institute for Cancer Research in Glasgow, UK. The Beatson Institute is a Cancer Research UK-funded centre which focuses on understanding cancer cell behaviour and developing new therapies and … Continue reading →... Read more »

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